The regulation of tumor growth by cytokine-induced alterations in host effector cell recruitment and activation is intimately associated with leukocyte adhesion and angiogenic modulation. We have developed a novel tumor model to investigate this complex series of events in response to cytokine administration. Gelatin sponges containing rhFGFb and B16F10 melanoma cells were implanted onto the serosal surface of the left lateral hepatic lobe in syngeneic C57BL/6 mice. The tumor model was characterized by progressive tumor growth initially localized within the sponge and the subsequent development of peritoneal carcinomatosis. Microscopic examination of the sponge matrix revealed well developed tumor associated vascular structures and areas of endothelial cell activation as evidenced by leukocyte margination. Treatment of mice three days post sponge implantation with a therapeutic regimen consisting of pulse rhIL-2 combined with rmIL-12 resulted in a marked hepatic mononuclear infiltrate and inhibition of tumor growth. In contrast to the control group, sponges from mice treated with rhIL-2/rmIL-12 demonstrated an overall lack of cellularity and vascular structure. The regimen of rhIL-2 in combination with rmIL-12 was equally effective against collagen sponge implants of rhFGFb/B16F10 melanoma in SCID mice treated with anti-asialo GM1 in the absence of a mononuclear infiltration, suggesting that T, B and/or NK cells were not the principal mediators of the anti-tumor response in this tumor model. The absence of vascularity within the sponge following treatment suggests that a potential mechanism of rhIL-2/rmIL-12 anti-tumor activity is the inhibition of neovascular growth associated with the establishment of tumor lesions, which could be dissociated from the known activities of these two cytokines to induce the recruitment and activation of host effector cells.